An oligomer‐directed Aβ antibody decreases synaptotoxic oligomeric Aβ in brain and improves behavioral abnormality in humanized APP knock‐in mice

Abstract

AbstractBackgroundThere is strong evidence that soluble oligomers of amyloid beta protein (oAβ) help initiate the pathogenic cascade of Alzheimer’s disease (AD), which suggests therapeutic strategies targeting oAβ over monomeric or fibrillar Aβ. A new antibody, 71A1, is 1∼00‐fold more sensitive for oAβ than synthetic monomers. The material that 71A1 specifically immunoprecipitates from AD soluble brain extracts impairs synaptic function as much as does the full extract. In accord, pre‐incubating brain extracts with 71A1 neutralizes its synaptotoxicity. 71A1 has potentially unique activities against disease‐relevant oAβ, making it a novel candidate for treating AD.Methods15 mg/kg 71A1 or anti‐KLH (negative control) was administered i.p. to 45 humanized APP knock‐in mice (APPNLGF/NLGF) weekly from 8 to 20 weeks of age. Cognition was assessed by spontaneous alternation (Y‐maze). Brains were harvested at age 21‐wk for biochemical, electrophysiological and immunohistochemical analyses. Diffusible (“soaking”) extracts of the brains were prepared to measure monomeric and oligomeric Aβ using homebrew ultra‐sensitive assays. Aliquots of the same soaking extracts were used to treat wild‐type mouse hippocampal slices and measure long‐term potentiation (LTP) to assess synaptotoxicity in the APPNLGF/NLGF brains post‐treatment.Results71A1 recognized oAβ and neutralized its synaptotoxicity in APPNLGF/NLGF mouse brain extracts. 71A1 effectively treated male APPNLGF/NLGF mice, which improved cognition significantly. The antibody reduced brain Aβ (1‐42) and oAβ levels with a trend toward statistical significance. Mouse brains with less oAβ had less synaptotoxicity as assessed by LTP.ConclusionsThese results demonstrate 71A1 is an oligomer‐preferring monoclonal antibody as a therapeutic candidate for AD, decreasing brain oAβ and oAβ‐induced synaptotoxicity. We believe this provides the first proof‐of‐concept mouse trial using an antibody that has been carefully characterized as oAβ‐preferring. We observed 1) a correlation between oAβ concentration and its synaptotoxicity; and 2) that 71A1 ameliorated aspects of cognitive impairment in APPNLGF/NLGF mice by targeting oAβ.